title: Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls.
abstract: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, and somatostatin to facilitate glucose disposal. The actions of incretin hormones are terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) and through renal clearance. GLP-1 and GIP promote β-cell proliferation and survival in rodents. DPP-4 inhibitors expand β-cell mass, reduce α-cell mass, and inhibit glucagon secretion in preclinical studies; however, whether incretin-based therapies sustain functional β-cell mass in human diabetic subjects remains unclear. GLP-1 and GIP exert their actions predominantly through unique G protein-coupled receptors expressed on β-cells and other pancreatic cell types. Accurate localization of incretin receptor expression in pancreatic ductal or acinar cells in normal or diabetic human pancreas is challenging because antisera used for detection of the GLP-1 receptor often are neither sufficiently sensitive nor specific to yield reliable data. This article reviews recent advances and controversies in incretin hormone action in the pancreas and contrasts established mechanisms with areas of uncertainty. Furthermore, methodological challenges and pitfalls are highlighted and key areas requiring additional scientific investigation are outlined.
authors.affiliation: Department of Medicine, Mt. Sinai Hospital, Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015153:Blotting, Western; D049109:Cell Proliferation; D006224:Cricetinae; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D054795:Incretins / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor